Mitochondrial dysfunction, mediated by changes in the production of ROS/RNS, plays an important role in the etiology of diabetes and offers a potential target for therapeutic intervention. Hyperglycemia results in progressive mitochondrial damage which can be assessed by changes in the mitochondrial proteome, cardiac dysfunction, and ultimately cell death. The underlying mechanisms leading to these changes have a major contribution from the post-translational modification of mitochondrial proteins and mitochondrial DMA. This proposal has the objective of developing mitochondrially targeted drugs that increase the degradation of intracellular ROS or RNS for the correction of the mitochondrial defects associated with hyperglycemia in cell and animal models of diabetes. It involves a consortium of investigators from the Medical College of Wisconsin and the University of Alabama at Birmingham and combines expertise in the measurement of ROS/RNS, the chemical synthesis of novel mitochondrially targeted antioxidants, mitochondrial proteomics and cell and animal models of diabetes. The consortium has the ability to design, characterize and optimize mitochondrial antioxidants in the large quantities necessary for assessment of efficacy in animal models of the disease. It is hypothesized that mitochondrially targeted antioxidants will ameliorate the ROS/RNS dependent modification of mitochondrial proteins, mtDNA damage and cardiac dysfunction that occurs in response to high glucose. This hypothesis will be examined using mitochondrial proteomics, cell biology and physiological approaches to model diabetes through pursuit of the following Specific Aims: 1: Synthesis and optimization of mitochondrially targeted antioxidants designed to decrease steady state levels of intra- mitochondrial superoxide, lipid radicals and peroxynitrite. Specific Aim 2: Screening of mitochondrially targeted antioxidants in cell culture systems. Specific Aim 3: Determine the impact of mitochondrially targeted antioxidants on mitochondrial dysfunction induced in an animal model of diabetes. The insights gained by the accomplishment of these specific aims will define the necessary elements for the successful design of mitochondrially targeted therapeutics. This would then act as the prelude to optimization of such compounds for clinical use in diabetes.